Influence of functional polymorphisms on susceptibility and chronic progression in the spirochetes induced hoof disease bovine digital dermatitis

功能多态性对螺旋体诱发蹄病牛指皮炎易感性和慢性进展的影响

• 批准号: 533845368
• 负责人: Dr. Diana Oelschlägel
• 金额: --
• 依托单位: Professur Tierzucht
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/533845368?language=en
• 关键词: Influence; functional; polymorphisms; susceptibility; chronic

Bovine digital dermatitis (BDD) is an infectious painful disease of the hoof in cattle with multifactorial etiology and a polygenic influence with respect to susceptibility and progression. A genome-wide association study performed by our working group led to the identification of two significantly associated single nucleotide polymorphisms. One polymorphism is located in the fifth exon of ASB16, the other downstream of CMPK2. Both of the mentioned genes are expected to be involved in immunological processes. Animals with these polymorphisms show a significantly higher probability to suffer from BDD and to develop chronical lesions. The findings on the genomic background concerning the pathogenesis will be an aid to establish a BDD pre-screening test and could be used in cattle breeding programs in the long term. In addition, further investigation of genetic factors and their effects will be addressed in order to improve existing therapeutic approaches and thus reduce the suffering of affected animals already in the short term. Currently, antibiotics offer a limited possibility for symptomatic treatment. However, permanent cure can only be achieved to a limited extent, as chronic reactivation of the painful inflammatory process often occurs after a period of rest. The aim of our proposed project is to gain more insight into the influence of identified polymorphisms on disease progression in the context of regulation of immunological signaling pathways and communication of locally involved cell types. The focus is on macrophages and keratinocytes, two important cell types involved in the inflammatory process. Transcriptome analyses from cell samples of animals with favorable or unfavorable genotype constellations will provide new information on differentially expressed inflammatory modulators, which will allow conclusions on the intercellular communication ability and the physiological functions of the cells and will be investigated and validated with appropriate follow-up experiments. Detailed knowledge about genetic variants and their cell biological effect on disease susceptibility and progression is also important for human medicine. Members of the bacterial class of spirochetes which include the BDD-associated Treponema species, are also involved in inflammatory, partially chronical diseases in humans, such as Lyme disease, syphilis or periodontitis. Therefore, polymorphisms are already being investigated as genetic predisposing factors in these infections since individual disease progression and variable efficiency of classical antibiotic therapies are known. Finally, with information on significantly associated polymorphisms and their effects at the molecular level, development of more effective, individualized prevention and treatment options for BDD will be enhanced, and bovine research could also provide useful insights across species.

牛指状皮炎(BDD)是一种牛的蹄部传染性疼痛疾病，具有多因素的病因和多基因的易感性和进展影响。我们的工作组进行的全基因组关联研究发现了两个显著相关的单核苷酸多态。一个多态性位于ASB16的第5个外显子，另一个位于CMPK2的下游。上述两个基因都有望参与免疫过程。具有这些多态的动物表现出明显更高的患BDD和发展成慢性病变的可能性。关于发病机制的基因组背景的研究结果将有助于建立BDD预筛查试验，并可长期用于牛的育种计划。此外，还将进一步研究遗传因素及其影响，以改进现有的治疗方法，从而在短期内减少受影响动物的痛苦。目前，抗生素为对症治疗提供了有限的可能性。然而，根治只能在有限的程度上实现，因为痛苦的炎症过程往往在休息一段时间后重新激活。我们建议的项目的目的是在免疫信号通路的调节和局部参与的细胞类型的交流的背景下，更深入地了解已识别的基因多态性对疾病进展的影响。重点是巨噬细胞和角质形成细胞，这是参与炎症过程的两种重要细胞类型。对具有有利或不利基因星座的动物的细胞样本进行转录组分析，将提供关于差异表达的炎症调节因子的新信息，这将使我们能够得出细胞间通讯能力和细胞生理功能的结论，并将通过适当的后续实验进行调查和验证。详细了解遗传变异及其对疾病易感性和进展的细胞生物学效应对人类医学也很重要。螺旋体的细菌类成员，包括与BDD相关的密螺旋体物种，也与人类的炎症性、部分慢性疾病有关，如莱姆病、梅毒或牙周炎。因此，基因多态作为这些感染的遗传易感因素已经被研究，因为个体疾病进展和经典抗生素疗法的不同疗效是已知的。最后，有了分子水平上显著相关的多态及其影响的信息，BDD更有效、更个性化的预防和治疗方案的开发将得到加强，牛的研究也可以提供跨物种的有用见解。